From studies of ovulation in mammals, it appears that gondadotropins, prostaglandins and certain other substances stimulate the release of plasminogen activator (PA) from follicle cells embedded in the ovarian stroma (Strickland, S., et al., (1976) J. Biol. Chem. 751:5694-5702) (FIG. 1). PA then stimulates the extracellular activation of plasminogen to plasmin. Plasmin is known to activate procollagenase to collagenase, which then degrades collagen.
Under pathological conditions, PA is also secreted by cancer cells, macrophages and virally transformed cells in a manner similar to follicle cells that have been hormonally stimulated (Unkeless, et al. (1974) J. Biol. Chem. 249:4295-4305) (FIG. 2). PA has been found in high concentrations in metastasizing lung tumors (Skriver, et al. (1984) J. Cell Biol. 99:753-758). PA has also been found in association with a variety of human tumors, as well as kidney and bladder carcinomas (Corasanti, et al. (1980) J. Natl. Canc. Inst. 65:345-351 Ladehoff, A. (1962) Act, Path. Micro. Scand. 55:273-280).
A particular role in the regulation of this mechanism has been proposed for lipoprotein(a) (Lp(a)), a low-density-lipoprotein-like particle that carries a unique glycoprotein, called apoprotein (a) (apo(a)). It has been proposed that this particle participates in wound healing and general cell repair (Brown, M., et. al., (1987) Nature 330:113-114). The cDNA sequence of apo(a) shows a striking homology to plasminogen, with multiple repeats of kringle 4, one kringle 5, and a protease domain. The isoforms of apo(a) vary in the range of 300 to 800 kDa and differ mainly in their genetically determined number of kringle 4 structures (McLean, J. W., et al.(1987) Nature 300:132-137). While apo(a) has no plasmin-like protease activity (Eaton, D. L., (1987) Proc. Natl. Acad. Sol. USA 84:3224-3228), serine protease activity has been demonstrated (Salonen, E.,et al. (1989) EMBO J. 8:4035-4040).
Despite its lack of functional homology, the strong structural similarity to plasminogen is decisive in the understanding of the physiological and pathological role of Lp(a). Like plasminogen, Lp(a) has been shown to bind lysine-sepharose, immobilized fibrin and fibrinogen, and the plasminogen receptor on endothelial cells (Harpel, P. C. et al.(1989) Proc. Natl. Acad. Sci. USA 86:3847-3851; Gonzalez-Gronow, M. et al.(1989) Biochemistry 28:2374-2377 Miles, L. et al.(1989) Nature 339:301-302 Hajjar, K. A., et al.(1989) Nature 339:303-305). Furthermore, Lp(a) has been shown to bind to other components of the arterial wall such as fibronectin and glycosaminoglycans. The precise nature of these bindings, however, is poorly understood.
Lp(a) plasma levels are found to be elevated in cancer, atherosclerosis and other diseases. Inversely, low levels of ascorbate have been associated with high incidences of these diseases (Knox, E. A. (1973) Lancet, i.e. 1465-1467; Wright, L. C. et al. (1989) Int. J. Cancer 43:241-244). Based on this and other observations, it was suggested that Lp(a) is a surrogate for ascorbate (Rath, M. & L. Pauling (1990) Proc. Natl. Acad. Sci. USA 87:6204-6207).
There exists a need for a therapeutic composition to reduce the degradation of the extracellular matrix, particularly due to plasmin-induced and free radical-induced proteolysis respectively fibrinolysis. Of particular value would be a composition that simultaneously reduces degradation and enhances collagen synthesis, the primary component of the extracellular matrix, and thereby help to prevent the proliferation of diseases.